- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Rydapt (midostaurin) / Novartis, Vanflyta (quizartinib) / Daiichi Sankyo
Journal: An Innovative Telomere-associated Prognosis Model in AML: Predicting Immune Infiltration and Treatment Responsiveness. (Pubmed Central) - Nov 7, 2024
This innovative TRG scoring model demonstrates considerable predictive value for AML patient prognosis, offering valuable insights for optimizing treatment strategies and personalized medicine approaches. The identified TRGs and associated scoring models could aid in risk stratification and guide tailored therapeutic interventions in AML patients.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, dovitinib (TKI258) / Novartis, Oncoheroes
Journal: Therapeutic Potental of Quinolin-2H-one Hybrids as Anticancer Agents. (Pubmed Central) - Sep 26, 2024
The current review presents information on the different quinolin-2-one hybrids and their effect on different cancer cell lines. It also imparts knowledge of the structural requirements for designing novel anticancer agents.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Zokinvy (lonafarnib) / Eiger
Preclinical, Journal: Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells. (Pubmed Central) - Jul 12, 2024
FTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Bosulif (bosutinib) / Pfizer, Lenvima (lenvatinib) / Eisai, Merck (MSD)
Review, Journal: An insight into sustainable and green chemistry approaches for the synthesis of quinoline derivatives as anticancer agents. (Pubmed Central) - Jul 10, 2024
The current review offers recent advances in quinoline derivatives as anticancer agents for green synthesis using microwave, ultrasound, and one-pot synthesis. We believe that our findings will provide useful insight and inspire more green research on this framework to produce powerful and selective quinoline derivatives.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Bosulif (bosutinib) / Pfizer, Tasigna (nilotinib) / Novartis, Inhibikase
Journal, Epigenetic controller: Identification of a signature of histone modifiers in kidney renal clear cell carcinoma. (Pubmed Central) - Jul 5, 2024
The results of the drug sensitivity analysis showed that the high-risk group was more sensitive to several chemotherapeutic agents such as Sunitinib, Tipifarnib, Nilotinib and Bosutinib than the low-risk group. In conclusion, we successfully constructed HMs-based prognostic signature that can predict the prognosis of KIRC.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Tipifarnib Reduces Extracellular Vesicles and Protects From Heart Failure. (Pubmed Central) - Jul 4, 2024
Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib-mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling in HF.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Farnesyltransferase inhibitor tipifarnib regulates platelet function through thromboxane A2 generation (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1370;
It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A2 (TxA2) generation, suggesting the important role of tipifarnib on TxA2 generation in platelets. Consistently, tipifarnib did not affect the dose-dependent 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA2 generation was blocked.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors. (Pubmed Central) - Apr 27, 2024
Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)...Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.
- |||||||||| FIT-001 / Guangzhou FineImmune Biotech, KO-2806 / Kura Oncology
FIT-001: A phase 1 clinical trial of the farnesyl transferase inhibitor KO-2806 alone or as part of combination therapy for advanced solid tumors. (Hall A; Poster Bd #: 302a) - Apr 24, 2024 - Abstract #ASCO2024ASCO_1772;
P1, P2
Recent clinical trials (NCT03719690, NCT02383927) of the FTI, tipifarnib, in patients with HRAS-mutant (HRAS-m) head and neck squamous cell carcinoma harboring high variant allele frequency mutations (VAF ?20%), showed objective response rates of up to 50% and favorable long-term outcomes...In preclinical studies, KO-2806 has been shown to: (1) enhance tumor growth inhibition of tyrosine kinase inhibitors, including cabozantinib, in multiple clear cell renal cell carcinoma (ccRCC) cell line- and patient-derived xenograft models; and (2) enhance activity of KRAS inhibitors, including adagrasib, in KRAS mutant non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC) mouse models...Other combination arms may also be considered. The study began accrual in October 2023.
- |||||||||| doxorubicin hydrochloride / Generic mfg., docetaxel / Generic mfg., gemcitabine / Generic mfg.
Systemic therapy in NF-1 associated malignant peripheral nerve sheath tumors (MPNST). (Hall A; Poster Bd #: 509) - Apr 24, 2024 - Abstract #ASCO2024ASCO_789;
In this study < 50% pts with advanced NF1 related MPNST made it to 2nd line CT and outcomes were inferior to the predominantly D based 1st line regimens. This highlights an area of high unmet need.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Biomarker, Enrollment change, Trial completion date, Trial primary completion date, Metastases: Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial (clinicaltrials.gov) - Apr 17, 2024
P2, N=5, Active, not recruiting,
This highlights an area of high unmet need. N=49 --> 5 | Trial completion date: Sep 2027 --> Apr 2025 | Trial primary completion date: Sep 2027 --> Mar 2024
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Trial termination, Metastases: Tipifarnib in Advanced Squamous NSCLC With Oncogen HRAS MutAtionS (clinicaltrials.gov) - Mar 28, 2024
P2, N=9, Terminated,
N=49 --> 5 | Trial completion date: Sep 2027 --> Apr 2025 | Trial primary completion date: Sep 2027 --> Mar 2024 Active, not recruiting --> Terminated; The recruitment was closed prematurely to due to slow recruitment.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Wild-type RAS signaling is an essential therapeutic target in RAS-mutated cancers (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4011;
The mutant HRAS inhibitor tipifarnib blocked PI3K signaling and synergized with MEK inhibitors in HRAS-mutated cancer cell lines; covalent KRASG12C inhibitors blocked MEK signaling and synergized with PI3K inhibitors in KRASG12C- mutated cell lines...Dual knock-out of WT RAS isoforms in KRAS- and HRAS-mutated cancer cell lines reduced PI3K signaling in KRAS-mutant cell lines and MAPK signaling in HRAS-mutant cell lines and reduced proliferation, confirming our findings in MEF cells. Overall, our data highlight the critical role of WT RAS isoforms in supporting mutant RAS signaling and should be considered when designing combination therapies in RAS-mutated cancers.
- |||||||||| Preclinical, Journal: In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies. (Pubmed Central) - Jan 16, 2024
We additionally modeled resistance to targeted therapies including the KRAS inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Biomarker, Enrollment closed, Metastases: Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial (clinicaltrials.gov) - Jan 3, 2024
P2, N=49, Active, not recruiting,
These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance. Recruiting --> Active, not recruiting
- |||||||||| Piqray (alpelisib) / Novartis, Zarnestra (tipifarnib) / Kura Oncology
Journal: To Tip or Not to Tip: A New Combination for Precision Medicine in Head and Neck Cancer. (Pubmed Central) - Oct 2, 2023
This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252.
- |||||||||| Lenvima (lenvatinib) / Eisai, Merck (MSD)
LENVATINIB IN COMBINATION WITH ONCOPROTEIN TARGETED MAPK INHIBITORS IN DIFFERENTIATED AND DEDIFFERENTIATED THYROID CANCERS () - Sep 20, 2023 - Abstract #ATA2023ATA_427;
Mice with dedifferentiated tumors treated with 4 weeks of either lenvatinib or dabrafenib/trametinib (dab/tram) for Braf/Arid1a or tipifarnib for Hras/p53 demonstrated tumor progression or stability (% change tumor volume: Braf/Arid1a: vehicle +238.0%, lenvatinib +170.4%, dab/tram +62.1%; Hras/p53: vehicle +600.4%, lenvatinib ?0.3%, tipifarnib +63.4%, vehicle vs all conditions in both models p?<?0.05) whereas treatment with lenvatinib in combination with the oncoprotein inhibitors significantly reduced tumor volume (% change tumor volume: Braf/Arid1a: lenvatinib + dab/tram ?64.2%; Hras/p53: lenvatinib/tipifarnib ?41.7%, all monotherapy vs combination therapy p?<?0.05 except lenvatinib vs lenvatinib/tipifarnib p?=?0.06). Combination MAPK signaling blockade and angiogenesis inhibition leads to profound anti?tumor responses across the spectrum of thyroid cancers in GEMMs.
- |||||||||| imatinib / Generic mfg.
Journal: Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib. (Pubmed Central) - Sep 19, 2023
Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Preclinical, Journal: Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor. (Pubmed Central) - Sep 11, 2023
Likewise, phase II clinical trials with erlotinib, which targets the epidermal growth factor (EFGR), and sorafenib, which targets the vascular endothelial growth factor receptor (VEGF), platelet-derived growth factor receptor (PDGF), and Raf, in combination with standard chemotherapy, have also failed to produce a response in patients...We then describe how to perform genome-scale shRNA screens to identify and compare critical signaling pathways in mouse and human MPNST cells and identify druggable targets in these pathways. These methodologies provide an effective approach to identifying new therapeutic targets in a variety of human cancer types.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology, Mekinist (trametinib) / Novartis
Genomic and transcriptomic profiling of inflammatory breast cancers and non-inflammatory breast cancers in Asian women. () - Apr 26, 2023 - Abstract #ASCO2023ASCO_4160;
Our study is the first to provide a complete genomic and transcriptomic landscape of IBC based on combined analysis of WES and RNA-seq and the first to focus on Asian women. We discovered intriguing differences unique in Asian women that could potentially explain IBC etiology and presented RAS signaling pathway as a potential therapeutic target in IBC treatment.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Rab27-dependent extracellular vesicle releasing participates in dengue virus non-structural protein 1 secretion (P713) (Exhibit Hall; Poster Board No. P713) - Apr 11, 2023 - Abstract #IMMUNOLOGY2023IMMUNOLOGY_1557;
The EV biogenesis and secretion inhibitor, Tipifarnib treatment decreases the levels of NS1 and nSMase 2 but not the levels of ALIX in the EVs. Taken together, this study not only provide the new insights of mechanisms in DENV NS1 secretion through Rab27-mediated vesicle trafficking but also valuable therapeutic targets to dengue disease.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Journal: Mutated HRAS activates YAP1-AXL signaling to drive metastasis of head and neck cancer. (Pubmed Central) - Apr 5, 2023
Tipifarnib treatment also reduced AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.
- |||||||||| Zarnestra (tipifarnib) / Kura Oncology
Enrollment closed, Metastases: Cardiovascular Safety Study of Tipifarnib in Patients With Advanced Solid Malignancies (clinicaltrials.gov) - Apr 5, 2023
P1, N=20, Active, not recruiting,
Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression. Recruiting --> Active, not recruiting
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